Our goal is to define the molecular mechanisms that control interactions between Cryptococcus neoformans and the mammalian immune system in an effort to ultimately prevent and treat fungal disease. Fungi are emerging pathogens, and morbidity and mortality are most apparent among the immunocompromised, especially in individuals with HIV/AIDS. The meningitis-causing fungus C. neoformans is particularly aggressive among people with AIDS, estimated to cause over a million cases of disease and ~600,000 deaths world-wide annually. The bulk of this burden is in Sub-Saharan Africa where the number of deaths from cryptococcal meningitis now appears to surpass the number of deaths from tuberculosis. In this region 13-44% of HIV/AIDS-related deaths are due to cryptococcosis, and mean survival times are on the order of a few weeks after onset. Worldwide, treatment with antifungal agents results in ~80% survival, and individual prognoses are strongly influenced by the availability of antifungal drugs and the immune status of the host. Little is known about the processes by which cryptococcal infection occurs, and we recognize a substantial gap in understanding the intersection between fungal pathogens and the host immune response. Studies over the last two decades have begun to define the relationships between C. neoformans yeast and the host immune system, but none has evaluated spores, likely infectious particles in nature. We have recently purified spores to homogeneity in numbers sufficient for comprehensive biochemical, molecular, and virulence studies. Using this novel reagent we have discovered that spores can cause disease in a mouse model and that murine alveolar macrophages, the first line of defense against respiratory fungal pathogens, interact fundamentally differently with spores than with yeast. Our findings place us in a unique position to ask questions about the C. neoformans-mammalian cell interface that have not been possible previously. We will take advantage of this major advance to investigate the fundamental properties of spores and their interactions with alveolar macrophages. Our hypothesis is that alveolar macrophages interact with spores via specific mechanisms that are distinct from those that mediate interactions with yeast. We will test our hypothesis by addressing the following three Aims. 1) Identify the receptors and ligands that mediate interactions between C. neoformans spores and murine alveolar macrophages. 2) Elucidate mechanisms that govern the ability of spores to survive inside macrophages. 3) Investigate the properties of spore-mediated disease using a murine model of infection. Our studies will provide insights fundamental to understanding how C. neoformans is recognized by the innate immune response and how cryptococcal disease is either suppressed in healthy individuals or disseminated in the immunocompromised. Ultimately, our findings promise to inform more general processes by which fungi cause disease, facilitating the discovery of novel prevention and/or treatment strategies.